A significant number of individuals die soon after a successful cardiopulmonary resuscitation form cardiac arrest, and of those that survive a significant fraction have residual neurological deficit. Most of the morbidity and mortality after initially successful resuscitation from cardiac arrest can be assigned to the immediate and delayed effects of reperfusion injury in the central nervous system. With aging, there is an increased incidence of cardiac arrest and subsequent death or residual neurological deficit secondary to reperfusion injury. This outcome is probably due to an increase in free radical production and decrease in defense mechanisms that exacerbates reperfusion injury in the aging. Nevertheless, the poor ability of the brain to recover from such reversible ischemic events remains, in all ages, unpromising and is most likely due to free radical damage and unstabilized energy metabolism. This project represents a new collaboration between investigators specializing in the area of reperfusion injury. We propose to investigate new treatment strategies aimed at using alternate energy substrates such as, pyruvate and ketones in combination with antioxidant type drugs, such as, melatonin, N-t-Butyl-a-Phenyl-nitrone, adenosine and methylisobutyl amiloride, as therapies for improving recovery from cardiac arrest. Novel esters will also be tested for their neuroprotective properties in brain against reperfusion injury. These compounds are unique in that they are metabolized to physiological substrates, such as, pyruvate, glycerol and N-acetylcyteine, and have shown to decrease the effects of reperfusion injury in other organ systems. An animal model of cardiac arrest and resuscitation, adult (3 mos) and aged (18 mos) rats will be used to test the efficacy of these new treatment strategies. One set of experimental protocols measures delayed loss of hippocampal CA1 neurons 4 and 30 days after cardiac arrest and resuscitation and survival rates. Another set of experimental protocols will elucidate specific mechanism(s) by which the selected energy substrates and agents and are effective.